Heparin is a polysaccharide drug with potent anticoagulant activity and is used in the prevention and treatment of thrombosis. It decreases the rate of coagulation by increasing the rate at which anti-thrombin inhibits activated coagulation factors such as thrombin, one of the key enzymes in the coagulation cascade. Certain heparinoids, heparin derivatives, heparin analogues, and other compounds that have heparin-like activity act as anticoagulants. Among all heparin and heparinoids, low molecular weight heparin is of particular interest from a clinical standpoint. Some of the low molecular weight heparins include enoxaparin, ardeparin, dalteparin, or the chemically synthesized heparin-like compound fondaparinux, a pentasaccharide.
Various studies suggest that low molecular weight heparinoids or heparin-like compounds may be associated with reduced risk of bleeding complications, have a longer half-life, and have reduced incidence of thrombocytopenia.
However, it is still difficult to handle low molecular weight heparinoids or heparin-like compounds, since they are fairly large molecules and have prominent negative charges, cannot be administered by oral delivery, and involve invasive delivery approaches. Hence it is necessary to formulate and deliver the drug in a dosage form which is chemically and physically stable to ensure efficacy and adequate patient compliance.
Fondaparinux sodium is a sodium salt form of fondaparinux, a synthetic pentasaccharide having antithrombotic activity. It acts by selectively binding to anti-thrombin III (ATIII), thereby potentiating the neutralization of factor Xa by ATIII. The neutralization of factor Xa interrupts the blood coagulation cascade and thereby inhibits thrombin formation and thrombus development. Fondaparinux does not inactivate thrombin and does not interact with platelet aggregation.
Chemically, fondaparinux sodium is methyl O-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-β-D-glucopyra-nuronosyl-(1→4)-O-2-deoxy-3,6-di-O-sulfo-2-(sulfoamino)-α-D-glucopyranosyl-(1→4)-O-2-O-sulfo-α-L-idopyranuronosyl-(1→4)-2-deoxy-6-O-sulfo-2-(sulfoamino)-α-D-glucopyranoside, decasodium salt. It has a molecular formula of C31H43N3Na10O49S8 and a molecular weight of 1728. The structure of fondaparinux sodium is represented by formula I:

Fondaparinux sodium is currently marketed by Mylan Ireland Ltd under the trade name ARIXTRA®. It is available as a sterile, preservative-free injectable solution of fondaparinux sodium for subcutaneous use, in a single dose prefilled syringe. As per the label approved by FDA, ARIXTRA® is indicated for the prophylaxis and treatment of thromboembolic diseases.
Formulations comprising fondaparinux sodium have been proposed in the literature. U.S. Pat. No. 9,089,484 discloses orally administrable pharmaceutical compositions comprising fondaparinux or a pharmaceutically acceptable salt thereof.
US patent application publication no. 20060014698 describes inhalational pharmaceutical compositions comprising fondaparinux.
Single dose formulations of heparin-like compounds such as fondaparinux sodium are available in the form of stable, preservative-free injectable solutions. Currently there are only single dose formulations of fondaparinux, available in the market as ARIXTRA®, provided in glass prefilled syringes. There are no multiple dose formulations of fondaparinux sodium available in the market nor in any form of literature in the public domain.
Prefilled syringes available in the market and used to deliver such products are administered as a unit dose, and may contain preservatives but require proper handling to prevent contamination. However, these syringes may not be capable of multidose administration on account of loss of sterility on first use. Furthermore, it has been noted that the stability and resultant efficacy of the drug product in itself—be it heparin; low molecular weight heparins, or such related molecules—is highly dependent on the nature of the formulation, material of the primary packing material used, and their mutual compatibility. It has been noted that impurity profiles of each of these molecules varies significantly with the change in packaging or container material. In addition, a change in the packaging or container requires extensive studies pertaining to the compatibility of the formulation to that of the packaging or container material. Therefore, it is important to provide the formulation (composition) in a device of appropriate primary packaging material.